Previous work from our group has shown that integrin 31 plays a critical role in the secretion of paracrine factors that promote both wound and tumor angiogenesis, highlighting the importance of integrin-mediated paracrine signaling from the epidermis to endothelial cells in the wound bed or tumor microenvironment. Unlike tumor angiogenesis, wound angiogenesis ultimately returns to a normalized state. Understanding how wound angiogenesis resolves may reveal aberrant processes in the tumor setting which could be exploited for targeted therapy. A major barrier to developing effective integrin-targeting therapies has been failure to identify key integrin-ECM interactions that work in a coordinated fashion to regulate tumor angiogenesis and other tumorigenic functions. The proposed work will address this knowledge gap by testing combinatorial roles for two integrins, 31 and 91. Both of these integrins are up-regulated in progressing squamous cell carcinoma (SCC) and in the activated wound epidermis. While it is known that these two integrins also exert distinct influences on keratinocyte function, preliminary data presented in this proposal clearly suggest a model in which many functions guided by 31 are tempered by 91. Furthermore, their ECM ligands are deposited into the provisional wound matrix at different times, suggesting temporal regulation of 31 and 91 in the wound setting. Indeed, while the 31 ligand, laminin-332 (LN-332), is deposited by activated keratinocytes immediately upon wounding, 91 ligand, cellular fibronectin (cFN), appears later in the provisional wound matrix. Upon expanding this study to an in vivo system, we observed that angiogenesis is compromised in wounds in which keratinocytes lack 31, but is aberrantly prolonged in wounds in which keratinocytes lack 91, suggesting that 91 acts as a brake on 31-dependent processes. Based on these preliminary data, we propose the novel hypothesis that 91 suppresses 31-dependent migration, as well as paracrine functions of the epidermis that promote angiogenesis. Furthermore, our model predicts that modulation of 31 function by 91 is regulated in a temporal manner, potentially by binding specific 91 ligands that are temporally or spatially regulated in wounds, and that such modulation is critical to regulating wound angiogenesis. Finally, we propose that this novel mode of integrin crosstalk regulates tumor invasion and angiogenesis as well. To test our hypothesis, we propose two Specific Aims: Aim 1: To determine mechanistically how 91 mediates cross-suppressive regulation of 31-dependent cellular functions and gene expression, in vitro; and Aim 2: To identify in vivo regulation of angiogenesis and/or tumorigenesis by 91-mediated cross-suppression of 31. Results from this work will improve our understanding of the roles that integrins play in promoting angiogenesis in both wounds and tumors, and it may facilitate the development of novel integrin-targeting therapeutics to inhibit cancer progression.